1. Field of the Invention
The present invention relates to novel pyrimidine derivatives having an aryl group at the 1-position and methods for treating allergic disorders therewith, particularly, methods for treating inflammatory allergic disorders such as asthma, dermatitis, rhinitis and the like, or graft-versus-host disease (GVHD) which occurs at organ transplantation.
2. Description of the Prior Art
Allergy is classified in four types I to IV. It is believed that so-called allergic disorders are mainly due to types I and IV. Atopic dermatitis has heretofore been believed to be an allergic disorder that is mainly due to type I allergy. However, in recent studies, it has been reported that atopic dermatitis is a disorder that is due to allergies of both types I and IV and in which the contribution of type IV is greater than that of type I. Type I allergy is called humoral immunity whereas type IV allergy is called cellular immunity. The mechanism of action is very different in the two types (Protein.Nucleic Acid.Enzyme, 36, 839-847 (1991)). In particular, there is a large difference in T cells that partake in their immunological mechanisms. Th.sub.2 cells play an important role in the type I allergy whereas Th.sub.1 cells do in the type IV allergy (J. Immunology, 138, 3688-3694 (1987)). In fact, commercially available therapeutic agents for type I allergy (e.g., anti-histamines, etc.) are not very effective against atopic dermatitis in clinical practice whereas steroid agents that exhibit effect on allergies of both types I and IV are clinically effective. Furthermore, it can be understood from the clinical effect of immunosuppresive agents (e.g., cyclosporine, FK-506, etc.) which are type IV allergy-inhibiting agents that type IV allergy is the main cause of atopic dermatitis. In other allergic disorders, for example, asthma, the cause of its initial onset is type I allergy but the subsequently occurring inflammation of the airway which may cause chronicity or incurability of asthma is due to type IV allergy (Allergy, 37, 12-18 (1988)). In addition, it has been experimentally found that type IV allergy can induce asthma and it has been reported that cyclosporine and the like are effective in the treatment of asthma (Amer. Rev. Resir. Dis., 144, 931-938 (1991); Allergy, 39, 482-487 (1990); and Allergy, 39, 605-609 (1990)). In the treatment of asthma, anti-type I allergic agents such as anti-histamines are administered only supplementally in mild cases and steroid agents are mainly used in the present situation.
For the aforementioned reasons, steroid agents that are effective against allergies of both types I and IV are administered in combination in the case of allergic disorders of a mixed type or those in which the contribution of type IV allergy is predominant. However, as is well known, clinically effective steroid agents cause various side-effects such as infectious diseases, adrenal retraction, osteoporosis, psychiatric disorders, diabetes and the like and are therefore unsuitable for long term or continuous administration. Hence, non-steroid compounds which are effective against both types I and IV can potentially be good therapeutic agents for a wide variety of allergic disorders and their development is desired.
There have been suggested several non-steroid compounds that are effective against allergic disorders. For example, the applicant has already proposed pyrimidine derivatives that are composed of a pyrimidine ring and a phenyl group, wherein the pyrimidine ring is substituted with various hydrocarbon groups at the 3- and 1-positioned nitrogen atoms and the phenyl group has lower alkyl substituents at the 3- and 5-positions and a hydroxy group at the 4-position, as disclosed in Japanese Patent Laid-Open Publication No. 5-194424; and uracil derivatives which are composed of an uracil ring and a phenyl group, wherein the uracil ring is substituted with various hydrocarbon groups at the 3- and 1-positioned nitrogen atoms and the phenyl group has lower alkyl substituents at the 3- and 5-positions and a hydroxy group at the 4-position, as disclosed in Japanese Patent Laid-Open Publication No. 6-135943.
Nevertheless, the development of novel non-steroid compounds having a better effect as therapeutic agents for allergic disorders of I and IV mixed type or those in which the contribution of type IV allergy is predominant is still desired strongly. In particular, there is a great demand for non-steroid compounds that can be administered orally and which are more suitable for long-term or continuous administration in the treatment of chronic allergic disorders such as atopic dermatitis, asthma and the like.